Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/09—Geometrical isomers
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

• the present invention relates to trans-isomeric heterocyclic compounds, i.e., piperidines, and a method of preparing these stereo-specific isomers.
• heterocyclic compounds e.g., piperidines
• possess pharmaceutical activity It has been reported that their pharmaceutical activity, as well as safety, varies based on the stereochemical configurations of the substituents on the piperidine ring. See, e.g., Pharmacia, 1989, 25(4), 311-336. Thus, effective synthesis of piperidines with high stereo-selectivity is of great importance.
• An aspect of the present invention is a method of preparing a trans-isomeric compound of formula (I) below or a pharmaceutically acceptable salt thereof:
• the method unexpectedly producing trans-isomeric piperidines in high yield and high stereo-selectivity, includes the step of hydrogenating a compound of formula (II) below or a pharmaceutically acceptable salt thereof:
• trans-isomeric compound of formula (I) having a trans:cis ratio of at least 70:30 (up to 99.9:0.1) or a pharmaceutically acceptable salt thereof, in which R 1 in formulas (I) and (II) is C 1 -C 5 alkyl or C 3 -C 5 cycloalkyl.
• the above-described method can further include a resolution step, which is performed via optical resolution of the trans-isomeric compound with an acidic resolving agent.
• This process can provide an optically enriched enantiomer of the trans-isomeric compound of formula (I) or a pharmaceutically acceptable salt thereof.
• the acidic resolving agent can be in R-form or S-form. If needed, the enantiomer thus obtained can be recrystallized with a recrystallization solvent.
• Another aspect of this invention is a trans-isomeric compound of formula (I) below or a pharmaceutically acceptable salt thereof:
• R 1 is C 1 -C 5 alkyl or C 3 -C 5 cycloalkyl and the trans-isomeric compound has a trans:cis ratio of at least 70:30.
• R 1 is C 1 -C 5 alkyl, e.g., methyl.
• trans-isomeric compound of formula (I) can be in the form of (3S, 5S)-configuration, i.e., formula (Ia) shown below, or (3R, 5R)-configuration, i.e., formula (Ib) also shown below:
• C 1 -C 5 alkyl herein refers to a straight or branched chain hydrocarbon radical containing 1 to 5 carbon atoms. Examples of C 1 -C 5 alkyl include, but are not limited to, methyl, ethyl, propyl, and isopropyl.
• C 3 -C 5 cycloalkyl refers to a saturated, cyclic hydrocarbon moiety containing 3 to 5 carbon atoms. Examples of C 3 -C 5 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, and cyclopentyl.
• Alkyl and cycloalkyl mentioned herein include both substituted and unsubstituted moieties, unless specified otherwise. Possible substituents on alkyl and cycloalkyl include, but are not limited to, amino, hydroxyl, halo, thio, acylamino, aminoacyl, aminothioacyl, amidino, guanidine, ureido, cyano, nitro, nitroso, azido, acyl, thioacyl, acyloxy, carboxyl, and carboxylic ester.
• a further aspect of this invention is a trans-isomeric compound of formula (I) prepared by the method described above.
• R 1 is C 1 -C 5 alkyl or C 3 -C 5 cycloalkyl.
• R 1 is C 1 -C 5 alkyl, e.g., methyl, ethyl, and isopropyl.
• the trans-isomeric compound has a trans:cis ratio of at least 70:30, e.g., 80:20, 90:10, and 99:1.
• the trans-isomeric compound can be present as a pure enantiomer.
• An exemplary enantiomer is in the form of (3S, 5S)-configuration of formula (Ia) shown in the SUMMARY section above or a pharmaceutically acceptable salt thereof, or in the form of (3R, 5R)-configuration of formula (Ib), also shown in the SUMMARY section above, or a pharmaceutically acceptable salt thereof.
• pharmaceutically acceptable salt refers to an acid or base salt of a compound of this invention.
• Preferred pharmaceutically acceptable salts include acid addition salts that can be formed by reacting the compound with a pharmaceutically acceptable acid, such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, aspartic acid, and glutamic acid.
• a pharmaceutically acceptable acid such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, maleic acid, lactic acid, malic acid,
• a salt for example, can be formed between an anion and a positively charged group (e.g., amino) on a compound having one of the above formulas.
• Suitable anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, malate, tosylate, tartrate, fumurate, glutamate, glucuronate, lactate, glutarate, and maleate.
• a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a compound having one of the above formulas.
• Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion.
• the compounds also include those salts containing quaternary nitrogen atoms.
• the weight of a compound mentioned herein refers to that of the free base form of that compound.
• prodrugs include esters and other pharmaceutically acceptable derivatives, which, upon administration to a subject, are capable of providing active compounds.
• a solvate refers to a complex formed between an active compound and a pharmaceutically acceptable solvent.
• pharmaceutically acceptable solvents include water, ethanol, isopropanol, ethyl acetate, acetic acid, and ethanolamine.
• the method includes hydrogenating a compound of formula (II), shown in the SUMMARY section above, with a palladium catalyst in the presence of an inert solvent to stereo-selectively produce a trans-isomeric compound of formula (I) having a trans:cis ratio of at least 70:30 or a pharmaceutically acceptable salt thereof.
• the stereo-selective hydrogenation of the compound of formula (II) is conducted in the presence of a palladium catalyst at a suitable pressure using a variety of solvents.
• the trans:cis ratios are determined by nuclear magnetic resonance (NMR) spectroscopy.
• the palladium catalyst includes one or more palladium compounds, such as Pd(OH) 2 /C, Pd/C, Pd(OAc) 2 , Pd/Al 2 O 3 , or a combination thereof. It optionally contains another transition metal catalyst, e.g., Pt/C and Rh/C.
• the content of palladium in the palladium catalyst can be about 0.01 wt % to about 30 wt %, or about 0.1 wt % to about 25 wt %, or about 1 wt % to about 20 wt %, or about 2 wt % to about 20 wt %, or about 5 wt % to about 20 wt %.
• the inert solvent examples include, but are not limited to, H 2 O, a C 1 -C 10 ester (e.g., ethyl acetate and methyl acetate), a C 3 -C 10 cycloalkane (e.g., cyclopropane, cyclobutane, cyclopentane, and cyclohexane), tetrahydrofuran (THF), dimethylformamide (DMF), acetonitrile, a C 1 -C 10 alcohol (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, ethylene glycol, propylene glycol, and butylenes glycol), an alkylene glycol monoalkyl ether (e.g., propylene glycol monomethyl ether, propylene glycol monoethyl ether, and propylene glycol monoprop
• an inert solvent can contain two or more C 1 -C 10 esters, two or more C 3 -C 10 cycloalkanes, and the like.
• an inert solvent can contain one or more inorganic acids (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid).
• the inert solvent is H 2 O, a C 1 -C 5 ester, a C 3 -C 6 cycloalkane, THF, DMF, acetonitrile, a C 1 -C 5 alcohol, propylene glycol monomethyl ether, propylene glycol monomethyl ether acetate, N,N-dimethylacetamide, a C 1 -C 5 carboxylic acid (e.g., formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, difluoroacetic acid, trifluoroacetic acid, and a combination thereof), a C 1 -C 5 sulfonic acid (e.g., methanesulfonic acid), or a combination thereof, optionally containing one or more inorganic acids of hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid.
• a C 1 -C 5 ester e.g., a C 3 -C 6
• the inert solvent is H 2 O, a C 1 -C 5 ester, a C 3 -C 6 cycloalkane, THF, DMF, a C 1 -C 5 alcohol, propylene glycol monomethyl ether, propylene glycol monomethyl ether acetate, N,N-dimethylacetamide, a C 1 -C 5 carboxylic acid, a C 1 -C 5 sulfonic acid, or a combination thereof, optionally containing hydrochloric acid.
• inert solvents H 2 O, methanol (MeOH), ethanol (EtOH), isopropanol (i-PrOH), ethyl acetate, formic acid, acetic acid, methanesulfonic acid, and a combination thereof, optionally containing hydrochloric acid.
• the inert solvent containing an inorganic acid is capable of providing extremely high stereo-selectivity of trans-isomeric piperidines.
• the inert solvent is an organic acid or a combination of the organic acid with one or more of the following solvents: H 2 O, a C 1 -C 10 ester, a C 3 -C 10 cycloalkane, THF, DMF, acetonitrile, an alkylene glycol monoalkyl ether, an alkylene glycol monoalkyl ether carboxylate, an amide-based solvent, a C 1 -C 10 alcohol, and an inorganic acid.
• the inert solvent is a C 1 -C 5 carboxylic acid, a C 1 -C 5 sulfonic acid, or a combination thereof, optionally combined with one or more solvents of H 2 O, a C 1 -C 10 ester, a C 3 -C 10 cycloalkane, THF, DMF, acetonitrile, an alkylene glycol monoalkyl ether, an alkylene glycol monoalkyl ether carboxylate, an amide-based solvent, a C 1 -C 10 alcohol, and an inorganic acid.
• the inert solvent is formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, or a combination thereof, optionally combined with one or more solvents of H 2 O, a C 1 -C 10 ester, a C 3 -C 10 cycloalkane, THF, DMF, acetonitrile, an alkylene glycol monoalkyl ether, an alkylene glycol monoalkyl ether carboxylate, an amide-based solvent, a C 1 -C 10 sulfonic acid, a C 1 -C 10 alcohol, and an inorganic acid.
• the inert solvent containing an organic acid e.g., a C 1 -C 5 carboxylic acid and a C 1 -C 5 sulfonic acid
• an organic acid e.g., a C 1 -C 5 carboxylic acid and a C 1 -C 5 sulfonic acid
• the inert solvent is a C 1 -C 5 ester, a C 3 -C 6 cycloalkane, THF, DMF, acetonitrile, a C 1 -C 5 alcohol, propylene glycol monomethyl ether, propylene glycol monomethyl ether acetate, N,N-dimethylacetamide, a C 1 -C 5 carboxylic acid, a C 1 -C 5 sulfonic acid, or a combination thereof, optionally combined with H 2 O.
• the hydrogenation reaction is carried out at 10-100° C., e.g., 15-80° C., 20-70° C., 20-60° C., 20-50° C., and 25-45° C. As examples, it is carried out at 25° C., 30° C., 35° C., 40° C., 45° C., 50° C., 55° C., or 60° C.
• the hydrogenation reaction can be carried out under a hydrogen pressure of 1-60 bar, 5-50 bar, 10-40 bar, 15-30 bar, or 15-25 bar.
• the hydrogenation reaction time varies within a wide range, e.g., 1-80 hours, depending on the palladium catalyst, the hydrogen pressure, the reaction temperature, and the hydrogenation facility used. Completion of the hydrogenation reaction can be confirmed by NMR. After completion, purification can be effected by filtration, concentration under reduced pressure, and distillation. Of note, the trans-isomeric piperidine thus obtained can be converted into a salt form, if needed.
• the hydrogenation reaction is carried out at 25-45° C. under a hydrogen pressure of 15-25 bar.
• trans-isomeric piperidine is typically obtained with a trans:cis ratio of 70:30 to 99.9:0.1 (e.g., 70:30 to 99:1, 70:30 to 95:5, 70:30 to 90:10, 75:25 to 99.9:0.1, 75:25 to 95:5, 75:25 to 90:10, 80:20 to 99.9:0.1, 80:20 to 99:1, 80:20 to 95:5, 80:20 to 90:10, 85:15 to 99.9:0.1, 85:15 to 99:1, 85:15 to 95:5, and 85:15 to 90:10).
• the preparation method described above can further include a resolution step, which is performed via optical resolution of the trans-isomeric piperidine thus obtained with an acidic resolving agent.
• This step provides an optically enriched enantiomer of the trans-isomeric compound of formula (I), i.e., (3S, 5S)- or (3R, 5R)-configuration enantiomer, or a pharmaceutically acceptable salt thereof in high yield and high purity.
• the acidic resolving agent can be in R-form or S-form.
• the enantiomer thus obtained can be further recrystallized with a recrystallization solvent.
• acidic resolving agent refers to an acidic compound that can lead to the precipitation of a diastereomer containing a suitable enantiomer in high chemical and optical yields.
• R 1 is C 1 -C 5 alkyl or C 3 -C 5 cycloalkyl.
• Two salt forms of the optical isomers containing (3S, 5S)-configuration Ia and (3R, 5R)-configuration Ib can each be obtained by optical resolution of the trans-isomeric compound of formula (I) with an acidic resolving agent.
• the enantiomeric excess value (i.e., “ee value”) of one enantiomer ((3S, 5S)-configuration Ia or (3R, 5R)-configuration Ib) is 70-100%, 80-100%, 90-100%, 95-100%, 99-100%, 70-99.9%, 80-99.9%, 85-99.9%, 90-99.9%, 95-99.9%, or 99-99.9%.
• ee value is the difference between the amounts of each of the enantiomers present in a mixture, relative to the total amount of the compound in the mixture expressed as percentage ( ⁇ 100%).
• the acidic resolving agent can be deoxycholic acid, ( ⁇ )-2,3:4,6-di-o-isopropylidene-2-keto-L-gulonic acid monohydrate, D-( ⁇ )-quinic acid, L-pyroglutamic acid, ( ⁇ )-monomethylsuccinate, N-acetyl-D-(+)-leucine, N-acetyl-L-methionine, (R)-(+)-N-(1-phenylethyl)succinamic acid, (S)-(+)-5-oxe-2-tetrahydrofurancarboxylic acid, (R)-(+)-N-(1-phenylethyl)phthalamic acid, ( ⁇ )-mono-(1R)-menthyl phthalate, ( ⁇ )-menthyloxyacetic acid, (S)-(+)-mandelic acid, L-(+)-tartaric acid, D-(+)-
• R-form and S-form of an acidic resolving agent e.g., (R)-( ⁇ )-naproxen and (S)-(+)-naproxen, can be used to acquire a high ee value.
• the acidic resolving agent is deoxycholic acid, D-( ⁇ )-quinic acid, ( ⁇ )-monomethylsuccinate, N-acetyl-D-(+)-leucine, N-acetyl-L-methionine, ( ⁇ )-mono-(1R)-menthyl phthalate, ( ⁇ )-dibenzoyl-L-tartaric acid anhydrous, ( ⁇ )-O,O′-dibenzoyl-L-tartaric acid mono(dimethylamide), D-(+)-10-camphorsulfonic acid, L-(+)-lactic acid, or (R)-( ⁇ )-naproxen.
• the optical resolution can be carried out in the presence of an inert solvent.
• an inert solvent Use of the inert solvent is well known in the art and varies depending on the type of the starting racemic trans-isomer of a piperidine compound and the resolving agent used.
• the inert solvent for optical resolution can be H 2 O, a C 1 -C 10 ester (e.g., ethyl acetate and methyl acetate), a C 3 -C 10 cycloalkane (e.g., cyclohexane), THF, DMF, acetonitrile, a C 1 -C 10 alcohol (e.g., MeOH, EtOH, n-PrOH, i-PrOH, n-BuOH, and i-BuOH), an alkylene glycol monoalkyl ether (e.g., propylene glycol monomethyl ether, propylene glycol monoethyl ether, and propylene glycol monopropyl ether), an alkylene glycol monoalkyl ether carboxylate (e.g.
• propylene glycol monomethyl ether acetate propylene glycol monoethyl ether acetate, and propylene glycol monopropyl ether acetate
• an amide-based solvent e.g. N,N-dimethylacetamide and N,N-dimethylformamide
• amide-based solvent e.g. N,N-dimethylacetamide and N,N-dimethylformamide
• the inert solvent is H 2 O, acetonitrile, ethyl acetate, C 1 -C 3 alcohol, or a combination thereof. Most preferably, the inert solvent is acetonitrile.
• the ratio of the inert solvent to a reaction substrate is not particularly restricted.
• the solvent can be used in an amount 0.5 to 100 times the weight of the substrate.
• the temperature for optical resolution varies depending on the type of the starting material, the resolving agent, and the solvent used.
• the reaction is typically performed at 20-60° C. (e.g., 30-50° C.).
• the optical resolution described above can further include a step of recrystallization of (3S, 5S)-configuration (Ia) or (3R, 5R)-configuration (Ib) with a recrystallization solvent to form a product with high optical purity.
• the recrystallization solvent can be H 2 O, a C 1 -C 10 ester (e.g., ethyl acetate and methyl acetate), a C 3 -C 10 cycloalkane (e.g., cyclohexane), THF, DMF, acetonitrile, a C 1 -C 10 alcohol (e.g., MeOH, EtOH, n-PrOH, i-PrOH, n-BuOH, and i-BuOH), an alkylene glycol monoalkyl ether (e.g., propylene glycol monomethyl ether, propylene glycol monoethyl ether, and propylene glycol monopropyl ether), an alkylene glycol monoalkyl ether carboxylate (e.g.
• an anti-solvent can also be employed during recrystallization.
• the term “anti-solvent” herein refers to a solvent in which a crystalline compound has limited or poor solubility.
• anti-solvent examples include, but are not limited to, ethyl acetate, acetone, methyl ethyl ketone, toluene, isopropyl acetate, and t-butyl methyl ether.
• Table 1 indicates that use of a non-palladium catalyst, i.e., Rh/C or Pt/C, resulted in a trans:cis ratio of 46:54 to 53:47 (Groups C1 and C2). In other words, no significant selectivity of diastereoisomers was observed. Unexpectedly, when using a palladium catalyst, the hydrogenation of compound (III) stereo-selectively produced compound (IV) favoring the formation of the trans-isomer with a trans:cis ratio of 73:27 to 78:22 (Groups E1 to E6).
• a non-palladium catalyst i.e., Rh/C or Pt/C
• Example 3 Stereoselective Hydrogenation of 5-methyl-nicotinamide in the Presence of HCl, H 2 O/MeOH, and Pd/C

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